In 2009, 344,000 people in Japan died from malignant neoplasm, which was the top cause of death. Among them, the number of deaths from hepatocellular carcinoma exceeded 30,000. The number of deaths by hepatocellular carcinoma has increased year by year and has almost tripled over the past 20 years.
Among the hepatocellular carcinoma cases in Japan, 90% or more have been reported to be persistent infection (chronic hepatitis) caused by hepatitis B virus (HBV, hereinafter may be referred to as HBV) and hepatitis C virus (HCV, hereinafter may be referred to as HCV). Thus, viral hepatitis is a key disease for the onset of hepatocellular carcinoma. Meanwhile, non-alcoholic steatohepatitis (hereinafter may be abbreviated to as “NASH”) is a type of hepatitis triggered by accumulation of fat in the liver. Oxidative stress on fatty liver, insulin resistance, proinflammatory cytokine, etc., lead to transition from fatty liver or aggravation of pathological condition. In recent years, cases of the metabolic syndrome have increased, and there are concerns about an increase of the onset of NASH, and subsequent transition to liver fibrosis, cirrhosis, and hepatocellular carcinoma. Thus, NASH as well as viral hepatitis is a key disease involved in the onset of hepatocellular carcinoma.
Currently, hepatocellular carcinoma is treated through, for example, techniques including surgical therapies (e.g., hepatectomy and liver transplantation); local medical therapies including percutaneous ethanol injection therapy, radiofrequency ablation, and percutaneous microwave coagulation therapy; catheterization such as transcatheter arterial embolization or hepatic artery reservoir therapy; and chemotherapy such as therapy by use of a molecular target drug. However, even in a current stage when these therapies are available, hepatocellular carcinoma has recurred at high occurrence. Specifically, within 2 years from the time of diagnosis, intrahepatic recurrence (secondary carcinogenesis) is observed in 28.8% of hepatocellular carcinoma patients (Non-Patent Document 1), and repetition of recurrence results in death of many patients. Therefore, in addition to early-stage detection and treatment of hepatocellular carcinoma, inhibition of transition from chronic hepatitis to hepatocellular carcinoma, and inhibition of recurrence of hepatocellular carcinoma after treatment thereof are thought to become important issues, and a therapy positively inhibiting recurrence of hepatocellular carcinoma in the remaining liver after treatment thereof is conceivably very important. However, at present, there has been established no therapeutic method for inhibiting recurrence of hepatocellular carcinoma.
Meanwhile, one pharmaceutical agent employed in the chemotherapy of hepatocellular carcinoma is a molecular target drug, sorafenib (trade name: Nexavar (registered trademark)). This drug is employed only in systemic chemotherapy for non-resectable hepatocellular carcinoma, and various severe adverse side effects are reported therewith. In addition, there have not been established efficacy and safety of adjuvant chemotherapy following the surgical or local medicinal therapy for hepatocellular carcinoma. Therefore, there is keen demand for an effective and safe drug which can be used after the surgical or local medicinal therapy for hepatocellular carcinoma.
As another compound, (2E,4E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,4,6,10,14-pentaenoic acid (hereinafter may be referred to as “peretinoin”) has been proven to have a hepatocellular carcinoma recurrence inhibitory action, from the clinical study result that recurrence of hepatocellular carcinoma after radical treatment thereof was significantly inhibited through long-term administration of the compound for one year. In addition, peretinoin causes substantially no liver disorders and provides no substantial adverse side effects which other retinoids provide, thereby serving as a safety drug (Non-Patent Document 2).
Meanwhile, branched-chain amino acids are used for ameliorating encephalopathy concomitant with chronic liver disorders, for ameliorating hypoalbuminemia of decompensated cirrhosis patients, who suffer hypoalbuminemia even under sufficient diet conditions, and for ameliorating other conditions. There has also been reported that a drug containing three branched-chain amino acids, isoleucine, leucine, and valine, has an inhibitory action on the onset and progress of hepatocellular carcinoma in patients of cirrhosis triggered by HCV. However, the above-reported research was limited to male patients of ages 25 to 75, and no effects are reported with respect to female patients or male patients outside the range of age. In addition, the report fails to describe or suggest that these drugs are effective on inhibition of recurrence of hepatocellular carcinoma after radical treatment thereof (Patent Document 1). Furthermore, there is a report describing that the drug containing the branched-chain amino acids is not potent to inhibition in recurrence of hepatocellular carcinoma after radical treatment thereof, from the viewpoints of either cumulative cancer recurrence rate or survival rate (Non-Patent Document 3). Thus, it has been suggested that inhibition of recurrence of hepatocellular carcinoma after the treatment thereof is more difficult than inhibition of onset and progress of hepatocellular carcinoma.